Among various types of cancers, lung cancer has the highest mortality rate in both men and women. The mortality rate of lung cancer in Japan has increased since 1950 and, as a result, the number of lung cancer deaths reached 50,871 in 1998, accounting for about 18% of all malignant tumor deaths. Since 1993, for men, the number of lung cancer deaths has surpassed that of stomach cancer deaths and has been ranked first among malignant tumors (see Non-patent Document 1). Furthermore, on the global scale, approximately 3,000,000 people are dying of lung cancer annually. Once diagnosed with tumor, systemic prognosis is poor, with the 5-year survival rate being mere 13%. However, an early detection and treatment of lung cancer can markedly improve the 5-year survival rate. If the disease is detected early and surgical resection is feasible, the 5-year survival rate increases to 40% (see Patent Document 1).
The basic histological types of lung cancer consist of adenocarcinoma, squamous cell carcinoma, adenosquamous carcinoma, large cell carcinoma and small cell carcinoma. Since the first four types are not largely different in terms of prognosis and therapeutic strategy, they are collectively referred to as non-small cell lung cancer.
The number of non-small cell lung cancer cases accounts for 80 to 85% of the number of all lung cancer cases. Non-small cell lung cancer is characterized by, for example, slow progression as compared to small cell carcinoma and insufficient response to chemotherapy and radiation therapy. Thus, during the stage when the tumor is localized, surgical resection is the first option; however, its treatment outcome is very poor as compared to other carcinomas such as stomach cancer at the same disease stage in the TNM classification. Although attempts have been actively made recently to improve the treatment outcome by multidisciplinary therapy, an effective therapeutic method that leads to complete remission has not been established yet. Therefore, an early detection is important and there is a demand for a simple and prompt test method with good sensitivity.
One example of a simple and prompt test method is measurement of a specific diagnostic marker in blood.
In order to achieve early detection of lung cancer and to improve the clinical management, serum biomarkers for lung cancer have been developed. Nonetheless, their clinical usefulness is still limited. For instance, the amounts of CEA (carcinoembryonic antigen) and CYFRA21-1 (cytokeratin 19 fragment) are elevated in sera of some of non-small cell carcinoma patients. Thus, CEA and CYFRA21-1 are clinically effective for monitoring the disease condition and evaluating the response to a treatment; however, they are not suitable for use in clinical diagnosis. This is because they are known to be associated with smoking and other diseases such as pneumonia as well as other types of cancer and they are thus not capable of detecting early-stage lung cancer (see Patent Document 2).
At present, in addition to the above-described markers, SCC (squamous cell carcinoma related antigens), SLX (sialyl Lewis x-i antigen) and the like are selected as blood diagnostic markers of non-small cell lung cancer and used individually or in combination; however, their positive detection rates for early-stage cancer are still low, and it is thus desired to develop a blood diagnostic marker that surely detects non-small cell lung cancer (see Non-patent Document 2). Furthermore, lung squamous cell carcinoma is known to be different from other non-small cell lung cancers in terms of responses to anticancer agents, and it is thus desired to develop a blood diagnostic marker that specifically detects lung squamous cell carcinoma (see Non-patent Document 3).
In squamous cell carcinoma, a large amount of glycoproteins of tumor cells are circulated into the body fluid of the circulatory system, such as serum, or bronchial secretions; therefore, enabling to detect a circulating antigen by ELISA using a monoclonal antibody is a feasible approach to early detection. Detection of tumor markers such as PSA and CEA corresponds to this approach (see Patent Document 1).
Desmoglein 3, which is a member of the cadherin family involved in cell adhesion, is a membrane protein molecule that is particularly highly expressed topically in the lung squamous cell carcinoma tissue, and its usefulness as a diagnostic marker of lung squamous cell carcinoma has been shown (see, for example, Patent Document 3 and Non-patent Document 3).
However, these previous reports all evaluated the expression of desmoglein 3 in cancer tissues by using mRNA or immunohistological staining, so that not only it was required to collect lung cancer tissues from patients by biopsy but also the subsequent analytical work was complicated; therefore, the methods used in these reports cannot be viewed as simple and prompt methods of examining lung squamous cell carcinoma.
Particularly, taking into consideration the properties, functional mechanism and the like of desmoglein 3 molecule, it is speculated that there is hardly any possibility for desmoglein 3 present in cancer tissues and the like to leak into blood. Thus, although there have been reports of studies on the use of a desmoglein 3-containing cadherin family molecule as a tumor marker to be detected by immunohistochemical staining (see Patent Document 3 and Non-patent Document 3), no study has been conducted on the use of desmoglein 3 as a serum marker. That is, the cell adhesion-related cadherin family molecules have a structural characteristic of being embedded in the cell membrane like an anchor and are largely different from other membrane proteins because of this feature.
Furthermore, the presence of an autoantibody for desmoglein 3 has been known, and it is detected even in the blood of a healthy individual. Accordingly, it is easily expected that, even if desmoglein 3 is present in blood, it would be neutralized or inactivated by the autoantibody. When the autoantibody is excessively expressed, it reacts with desmoglein 3 involved in the adhesion of normal skin cells and inhibits the adhesion, and this appears as an autoimmune disease called pemphigus. Even in the blood of healthy individuals and non-pemphigus patients in which the autoantibody is not excessively expressed, the autoantibody is detected in a trace amount.